AR089182A1 - AMINOPIRIMIDINE DERIVATIVES AS MODULATORS OF LRRK2 - Google Patents

AMINOPIRIMIDINE DERIVATIVES AS MODULATORS OF LRRK2

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Publication number
AR089182A1
AR089182A1 ARP120104438A ARP120104438A AR089182A1 AR 089182 A1 AR089182 A1 AR 089182A1 AR P120104438 A ARP120104438 A AR P120104438A AR P120104438 A ARP120104438 A AR P120104438A AR 089182 A1 AR089182 A1 AR 089182A1
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Argentina
Prior art keywords
alkyl
cycloalkyl
optionally substituted
halogen
alkoxy
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ARP120104438A
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Spanish (es)
Inventor
Gunzner-Toste Janet
Baker-Glenn Charles
Jon Burdick Daniel
Chambers Mark
K Chan Bryan
Chen Huifen
Estrada Anthony
Shore Daniel
Sweeney Zachary
Wang Shumei
Zhao Guiling
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Hoffmann La Roche
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Publication of AR089182A1 publication Critical patent/AR089182A1/en

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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

Los compuestos son útiles para el tratamiento de enfermedades asociadas con el receptor de la LRRK2, por ejemplo la enfermedad de Parkinson. Reivindicación 1: Compuestos de la fórmula (1) o sales farmacéuticamente aceptables de los mismos, en la que: m es un número de 0 a 3; X es: -NRᵃ-; -O-; o -S(O)ʳ-, en el que r es un número de 0 a 2 y Rᵃ es hidrógeno o alquilo C₁₋₆; R¹ es: alquilo C₁₋₆; alquenilo C₂₋₆; alquinilo C₂₋₆; haloalquilo C₁₋₆; (alcoxi C₁₋₆)-alquilo C₁₋₆; hidroxi-alquilo C₁₋₆; amino-alquilo C₁₋₆; (alquilsulfonil C₁₋₆)-alquilo C₁₋₆; cicloalquilo C₃₋₆ opcionalmente sustituido por alquilo C₁₋₆ o halógeno; (cicloalquil C₃₋₆)-alquilo C₁₋₆, cuya porción cicloalquilo C₃₋₆ está opcionalmente sustituida por alquilo C₁₋₆; tetrahidropiranilo; tetrahidrofuranilo; tetrahidrofuranil-alquilo C₁₋₆; oxetanilo; u oxetanil-alquilo C₁₋₆; o R¹ y Rᵃ junto con los átomos, a los que están unidos, pueden formar un anillo de tres a seis eslabones que opcionalmente puede incluir un heteroátomo adicional elegido entre O, N y S, y que está sustituido por oxo, halógeno o alquilo C₁₋₆; R² es: halógeno; alcoxi C₁₋₆; ciano; alquinilo C₂₋₆; alquenilo C₂₋₆; haloalquilo C₁₋₆; halo-alcoxi C₁₋₆; cicloalquilo C₃₋₆, cuya porción cicloalquilo C₃₋₆ está opcionalmente sustituida por alquilo C₁₋₆; (cicloalquil C₃₋₆)-alquilo C₁₋₆, cuya porción cicloalquilo C₃₋₆ está opcionalmente sustituida por alquilo C₁₋₆; tetrahidrofuranilo; tetrahidrofuranil-alquilo C₁₋₆; acetilo; oxetanilo; u oxetanil-alquilo C₁₋₆; R³ᵃ es: -OR⁴; halógeno; ciano; alquilo C₁₋₆; haloalquilo C₁₋₆; cicloalquilo C₃₋₆ opcionalmente sustituido por alquilo C₁₋₆; (cicloalquil C₃₋₆)-alquilo C₁₋₆, cuya porción cicloalquilo C₃₋₆ está opcionalmente sustituida por alquilo C₁₋₆; tetrahidrofuranilo; tetrahidrofuranil-alquilo C₁₋₆; oxetanilo; u oxetanil-alquilo C₁₋₆; R³ᵇ es: hidrógeno, o R³ᵃ y R³ᵇ junto con los átomos, a los que están unidos, pueden formar un anillo de cinco o seis eslabones, que incluye opcionalmente uno o dos heteroátomos, cada uno de ellos se elige con independencia entre O, N y S, dicho anillo está opcionalmente sustituido una o varias veces por R⁸; R⁴ es: hidrógeno; alquilo C₁₋₆; haloalquilo C₁₋₆; (alcoxi C₁₋₆)-alquilo C₁₋₆; cicloalquilo C₃₋₆ opcionalmente sustituido por alquilo C₁₋₆ o halógeno; (cicloalquil C₃₋₆)-alquilo C₁₋₆, cuya porción cicloalquilo C₃₋₆ está opcionalmente sustituida por alquilo C₁₋₆ o halógeno; tetrahidrofuranilo; tetrahidrofuranil-alquilo C₁₋₆; oxetanilo; u oxetanil-alquilo C₁₋₆; R⁵ es: hidrógeno; o alquilo C₁₋₆; R⁶ es: hidrógeno; alquilo C₁₋₆; (alcoxi C₁₋₆)-alquilo C₁₋₆; hidroxi-alquilo C₁₋₆; amino-alquilo C₁₋₆; cicloalquilo C₃₋₆; (cicloalquil C₃₋₆)-alquilo C₁₋₆; heteroarilo, heterociclilo; o heterociclil-alquilo C₁₋₆; dichos cicloalquilo C₃₋₆, (cicloalquil C₃₋₆)-alquilo C₁₋₆, heteroarilo, heterociclilo y heterociclil-alquilo C₁₋₆ pueden estar en cada caso opcionalmente sustituidos por uno, dos, tres o cuatro grupos elegidos con independencia entre: alquilo C₁₋₆; haloalquilo C₁₋₆; alcoxi C₁₋₆; halo-alcoxi C₁₋₆; hidroxi; hidroxi-alquilo C₁₋₆; halógeno; nitrilo; (alquil C₁₋₆)-carbonilo; (alquil C₁₋₆)-sulfonilo; cicloalquilo C₃₋₆; (cicloalquil C₃₋₆)-alquilo C₁₋₆; (cicloalquil C₃₋₆)-carbonilo; amino; y heterociclilo; o dos de los grupos junto con los átomos, a los que están unidos, pueden formar un anillo de cinco o seis eslabones; o R⁵ y R⁶ junto con el átomo de nitrógeno al que están unidos forman un anillo de tres a siete eslabones, que opcionalmente incluye un heteroátomo adicional elegido entre O, N y S(O)ₙ, y que está opcionalmente sustituido por uno, dos, tres o cuatro grupos elegidos con independencia entre: alquilo C₁₋₆; haloalquilo C₁₋₆; alcoxi C₁₋₆; halo-alcoxi C₁₋₆; hidroxi; (alcoxi C₁₋₆)-alquilo C₁₋₆; hidroxi-alquilo C₁₋₆; halógeno, nitrilo; (alquil C₁₋₆)-carbonilo; (alquil C₁₋₆)-sulfonilo; cicloalquilo C₃₋₆; (cicloalquil C₃₋₆)-alquilo C₁₋₆; (cicloalquil C₃₋₆)-carbonilo; amino; o heterociclilo; o dos de los grupos junto con los átomos, a los que están unidos, pueden formar un anillo de cinco o seis eslabones; y R⁷ es: halógeno; alquilo C₁₋₆; alcoxi C₁₋₆; haloalquilo C₁₋₆; o halo-alcoxi C₁₋₆; R⁸ es: halógeno; alquilo C₁₋₆; u oxo.The compounds are useful for the treatment of diseases associated with the LRRK2 receptor, for example Parkinson's disease. Claim 1: Compounds of the formula (1) or pharmaceutically acceptable salts thereof, wherein: m is a number from 0 to 3; X is: -NRᵃ-; -OR-; or -S (O) ʳ-, in which r is a number from 0 to 2 and Rᵃ is hydrogen or C₁₋₆ alkyl; R¹ is: C₁₋₆ alkyl; C₂₋₆ alkenyl; C₂₋₆ alkynyl; C₁₋₆ haloalkyl; (C₁₋₆ alkoxy) -C₁₋₆ alkyl; hydroxy-C₁₋₆ alkyl; amino C alkyl; (C₁₋₆ alkylsulfonyl) -C₁₋₆ alkyl; C₃₋₆ cycloalkyl optionally substituted by C₁₋₆ alkyl or halogen; (C₃₋₆ cycloalkyl) -C₁₋₆ alkyl, whose C cuya cycloalkyl portion is optionally substituted by C₁₋₆ alkyl; tetrahydropyranyl; tetrahydrofuranyl; tetrahydrofuranyl-C₁₋₆ alkyl; oxetanyl; or oxetanyl-C₁₋₆ alkyl; or R¹ and Rᵃ together with the atoms, to which they are attached, can form a ring of three to six links that may optionally include an additional heteroatom chosen from O, N and S, and which is substituted by oxo, halogen or C₁ alkyl ₋₆; R² is: halogen; C₁₋₆ alkoxy; cyano; C₂₋₆ alkynyl; C₂₋₆ alkenyl; C₁₋₆ haloalkyl; C₁₋₆ haloalkoxy; C₃₋₆ cycloalkyl, whose C ciclo cycloalkyl portion is optionally substituted by C₁₋₆ alkyl; (C₃₋₆ cycloalkyl) -C₁₋₆ alkyl, whose C cuya cycloalkyl portion is optionally substituted by C₁₋₆ alkyl; tetrahydrofuranyl; tetrahydrofuranyl-C₁₋₆ alkyl; acetyl; oxetanyl; or oxetanyl-C₁₋₆ alkyl; R³ᵃ is: -OR⁴; halogen; cyano; C₁₋₆ alkyl; C₁₋₆ haloalkyl; C₃₋₆ cycloalkyl optionally substituted by C₁₋₆ alkyl; (C₃₋₆ cycloalkyl) -C₁₋₆ alkyl, whose C cuya cycloalkyl portion is optionally substituted by C₁₋₆ alkyl; tetrahydrofuranyl; tetrahydrofuranyl-C₁₋₆ alkyl; oxetanyl; or oxetanyl-C₁₋₆ alkyl; R³ᵇ is: hydrogen, or R³ᵃ and R³ᵇ together with the atoms, to which they are attached, can form a ring of five or six links, which optionally includes one or two heteroatoms, each of which is independently chosen from O, N and S, said ring is optionally substituted once or several times by R⁸; R⁴ is: hydrogen; C₁₋₆ alkyl; C₁₋₆ haloalkyl; (C₁₋₆ alkoxy) -C₁₋₆ alkyl; C₃₋₆ cycloalkyl optionally substituted by C₁₋₆ alkyl or halogen; (C₃₋₆ cycloalkyl) -C₁₋₆ alkyl, whose C cuya cycloalkyl portion is optionally substituted by C₁₋₆ alkyl or halogen; tetrahydrofuranyl; tetrahydrofuranyl-C₁₋₆ alkyl; oxetanyl; or oxetanyl-C₁₋₆ alkyl; R⁵ is: hydrogen; or C₁₋₆ alkyl; R⁶ is: hydrogen; C₁₋₆ alkyl; (C₁₋₆ alkoxy) -C₁₋₆ alkyl; hydroxy-C₁₋₆ alkyl; amino C alkyl; C₃₋₆ cycloalkyl; (C₃₋₆ cycloalkyl) -C₁₋₆ alkyl; heteroaryl, heterocyclyl; or heterocyclyl-C₁₋₆ alkyl; said C₃₋₆ cycloalkyl, (C₃₋₆ cycloalkyl) -C₁₋₆ alkyl, heteroaryl, heterocyclyl and heterocyclyl-C alquilo alkyl may in each case be optionally substituted by one, two, three or four groups independently selected from: alkyl C₁₋₆; C₁₋₆ haloalkyl; C₁₋₆ alkoxy; C₁₋₆ haloalkoxy; hydroxy; hydroxy-C₁₋₆ alkyl; halogen; nitrile; (C₁₋₆ alkyl) -carbonyl; (C₁₋₆ alkyl) -sulfonyl; C₃₋₆ cycloalkyl; (C₃₋₆ cycloalkyl) -C₁₋₆ alkyl; (C₃₋₆ cycloalkyl) -carbonyl; Not me; and heterocyclyl; or two of the groups together with the atoms, to which they are attached, can form a ring of five or six links; or R⁵ and R⁶ together with the nitrogen atom to which they are attached form a ring of three to seven links, which optionally includes an additional heteroatom chosen from O, N and S (O) ₙ, and which is optionally substituted by one, two , three or four groups chosen independently from: C₁₋₆ alkyl; C₁₋₆ haloalkyl; C₁₋₆ alkoxy; C₁₋₆ haloalkoxy; hydroxy; (C₁₋₆ alkoxy) -C₁₋₆ alkyl; hydroxy-C₁₋₆ alkyl; halogen, nitrile; (C₁₋₆ alkyl) -carbonyl; (C₁₋₆ alkyl) -sulfonyl; C₃₋₆ cycloalkyl; (C₃₋₆ cycloalkyl) -C₁₋₆ alkyl; (C₃₋₆ cycloalkyl) -carbonyl; Not me; or heterocyclyl; or two of the groups together with the atoms, to which they are attached, can form a ring of five or six links; and R⁷ is: halogen; C₁₋₆ alkyl; C₁₋₆ alkoxy; C₁₋₆ haloalkyl; or halo-C₁₋₆ alkoxy; R⁸ is: halogen; C₁₋₆ alkyl; or oxo.

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